Synthesis of aromatic natural product frameworks using enyne metathesis

Article abstract of DOI:10.1016/S0040-4039(01)01313-2

Enynes, easily obtained by the Sonogashira coupling reactions of aromatic iodides, undergo, with good yields, enyne metathesis using the Grubbs catalyst. The resulting dienes are interesting carbo- and heterocycles which can give complex natural framework

Full text of DOI:10.1016/S0040-4039(01)01313-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7029–7031
Synthesis of aromatic natural product frameworks using
enyne metathesis
Marta Rosillo, Luis Casarrubios, Gema Dom´ınguez and Javier Pe´rez-Castells*
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de CC. Experimentales y Tecnicas, Universidad San Pablo-CEU,
Urb. Montepr´ıncipe, Boadilla del Monte 28668 Madrid, Spain
Received 19 April 2001; accepted 20 July 2001
Abstract—Enynes, easily obtained by the Sonogashira coupling reactions of aromatic iodides, undergo, with good yields, enyne
metathesis using the Grubbs catalyst. The resulting dienes are interesting carbo- and heterocycles which can give complex natural
frameworks by Diels–Alder reactions. Thus, an estradiol type skeleton is obtained in two steps from the corresponding enynes.
An example of a metathesis-Diels–Alder cascade one-pot process is reported. © 2001 Elsevier Science Ltd. All rights reserved.
Multiple bond metathesis reactions have become syn-
thetically powerful tools to achieve molecular complex-
ity in an elegant way.1 Among the different possibilities,
the ring closing alkene–alkyne reaction is the one which
has received less attention.2 This process formally
implies the formation of a carbonꢀcarbon bond and the
migration of the alkylidene part onto the alkyne car-
bon, to form a diene (Fig. 1). On the contrary to other
metathesis reactions, the mechanism is not completely
clear.
esting dienes which can be used in Diels–Alder reac-
tions. The combination of enyne metathesis followed by
Diels–Alder reactions has been recently explored for the
synthesis of other compounds like perhydroindenes,4
tetrahydropyridines5 or polycyclic-b-lactams.6 Thus, we
have prepared a series of enynes following Scheme 1.
The starting products were the 2-trimethylsilylethynyl
substituted phenol, aniline and benzaldehyde 1–3
obtained by Sonogashira coupling from the corre-
sponding iodo compounds.7 The allyl and homoallyl
ethers 4 were obtained by Mitsunobu reactions. Amides
5 were synthesized by alkylation of the corresponding
acetamide in phase transfer conditions with allyl and
The use of aromatic enynes has hardly been reported in
this reaction.3 These compounds can be easily prepared
and, after the metathesis process, would lead to inter-
PCy3
Cl
Cl
Ph
Ru
RuLn
PCy3
Figure 1.
H
TMS
H
(CH2)n
(CH2)n
XH
1,2,3
X
OR
X= O, n= 1, 2, 4a-b
X= NAc, n= 1, 2, 5a-b
R= H, n= 0, 6a
X=O, NH, CO
R= TBS, n= 0, 1, 2, 6b-d
Scheme 1.
* Corresponding author. Fax: 34913510475; e-mail: jpercas@ceu.es
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01313-2

7030
M. Rosillo et al. / Tetrahedron Letters 42 (2001) 7029–7031
the dienes 7 with good yields. Alcohol 6a gave the
corresponding diene, which could only be observed in
the spectrum of the crude mixture. This reaction
product decomposed after few hours at room tempera-
ture. All attempts to isolate it were unsuccessful. In
addition, no reaction was observed with the TBS pro-
tected compound 6b. We opted thus to react 6a and
protect the hydroxydiene in the crude mixture obtain-
ing 9b with 50% yield after the two reaction steps. On
the other hand, the TBS protected compounds 6c and
6d reacted smoothly to give the dienes 9c–d with good
yields. Amides 5a–b reacted with excellent yields.9
homoallyl bromide. The reaction of an appropriate
Grignard reagent with 1 (X=CO), and further protec-
tion of the resulting alcohol allowed us to obtain sub-
strates 6.
These substrates were submitted to metathesis using 7%
of Grubbs catalyst and the reactions were carried out in
refluxing dichloromethane.8 Among the different sol-
vents used (toluene, benzene), and catalyst proportions
(3, 5, 7 and 10%), these were the conditions which gave
better results. Table 1 summarizes the results obtained
in these reactions.
The yields summarized in Table 1 go from reasonable
to good in all cases but some comments ought to be
made. The reaction of the two ethers 4, gave only 50%
conversion after 2 h, and was not improved after 18 h
or when adding more catalyst to the reaction. Thus, we
added a total of 10% of catalyst divided into four equal
portions, which were added every 30 min. Before each
addition, the reaction mixture was filtered trough
Celite. With this procedure, the remaining starting
material was reduced to less than 10% and we isolated
The dienes obtained in these metathesis reactions are
related to Dane’s diene which has been much used as
starting material for the synthesis of several natural
products.10 In particular, the Diels–Alder reactions with
suitable dienophiles would lead to tetracyclic structures.
Thus, we carried out the synthesis of substrate 11 by
reduction of the hydroxyl group in compound 10 with
superhydride (Scheme 2).11 The metathesis reaction
proceeded with good yield (70%), and the obtained
diene 12 gave, upon reaction with maleic anhydride, a
Table 1. Synthesis of dienes 7–9
H
Grubbs cat. 7%
CH2Cl2,
( )n
( )n
∆
X
X
4-6
7-9
Entry
Substrate
X
n
Product
Yield (%)a
1
2
3
4
5
6
7
8
4a
4b
5a
5b
6a
6b
6c
6d
O
O
NAc
NAc
CHOH
CHOTBS
CHOTBS
CHOTBS
1
2
1
2
0
0
1
2
7a
7b
8a
8b
9b
N.R.
9c
65b
60b
95
85
50c
–
85
85
9d
a Of pure material with correct spectroscopic data (1H, 13C NMR, IR).
b 10% of total catalyst was added in four portions after filtration.
c Yield corresponds to TBS protected product 9b obtained from the crude mixture of the metathesis reaction.
LiBEt3H
7% Grubbs’
OH
10
(80%)
(70%)
11
12
O
O
O
O
O
O
H
H
O
O
O
H
H
H
H
Toluene, 35oC
3 days
rac-13, Major isomer, 50%
rac-14, Minor isomer, 10%
Scheme 2.

M. Rosillo et al. / Tetrahedron Letters 42 (2001) 7029–7031
7031
O
O
O
H
H
O
H
O
O
1) Grubbs 7%
H
CH2Cl2, ∆
O
O
2)
PhBr, ∆
(75%)
O
N
N
N
Ac
Ac
CH2Cl2, ∆
Ac
8a
5a
rac-15
(85%)
Scheme 3.
3:1 mixture isomers where major adduct, rac-13, was
isolated in 50% yield, and minor compound rac-14 in
10% yield. These compounds were assigned as the
stereoisomers depicted in Scheme 2 by analogy with
related structures described by Go¨bel.10a
Int. Ed. Engl. 2000, 39, 2073; (c) Armstrong, S. K. J.
Chem. Soc., Perkin Trans. 1 1998, 371; (d) Grubbs, R.
H.; Chang, S. Tetrahedron 1998, 54, 4413; (e) Fu¨rstner,
A. Top. Organomet. Chem. 1998, 1, 37.
2. Examples of enyne metathesis: (a) Bentz, D.; Lastchat,
S. Synthesis 2000, 1766; (b) Smulik, J. A.; Diver, S. T.
J. Org. Chem. 2000, 65, 1788; (c) Trost, B. M.; Doharty,
G. A. J. Am. Chem. Soc. 2000, 112, 3801; (d) Stragies,
R. S.; Voigtmann, U.; Bletchert, S. Tetrahedron Lett.
2000, 41, 5465; (e) Smulik, J. A.; Diver, S. T. Org. Lett.
2000, 2, 2271; (f) Mori, N.; Kitamura, T.; Sakakibara,
N.; Sato, Y. Org. Lett. 2000, 2, 543.
On the other hand, compound 8a reacted with maleic
anhydride only in refluxing bromobenzene, yielding,
after 2 h, 75% of compound rac-15 (endo adduct). A
minor isomer of this compound was detected in less
than 10% amount in the crude 1H NMR spectrum
(Scheme 3). The relative configuration of this adduct
was determined by analogy with previously reported
compounds.12 In order to avoid these severe reaction
conditions we tried the one-pot obtention of compound
rac-15 by adding the dienophile to the metathesis reac-
tion mixture, once total conversion of the enyne was
verified (TLC). We were very pleased to obtain the final
pure tetracyclic compound rac-15 in 85% overall yield,
after 36 h of reaction in refluxing dichloromethane.
This result shows the possible catalytic action of the
ruthenium complex in the Diels–Alder reaction. We are
currently investigating the generality of this process
with other enynes and dienophiles.
3. Lane, C.; Snieckus, V. Synlett 2000, 1294.
4. Bentz, D.; Laschat, S. Synthesis 2000, 1766.
5. Schurer, S. C.; Blechert, S. Tetrahedron Lett. 1999, 40,
1877.
6. Duboc, R.; He´naut, C.; Savignac, M.; Genet, J.-P.;
Bhatnagar, N. Tetrahedron Lett. 2001, 42, 2461.
7. Bergman, J.; Venemalm, L. J. Org. Chem. 1992, 57,
2495.
8. General procedure follows: 1 mmol of enyne is dissolved
in 20 mL of dry dichloromethane under argon. To this
solution, 0.07 mmol of benzylidene-bis(tricyclo-
hexylphosphine)–dichlororuthenium is added and the
reaction refluxed for 5–15 h (TLC). Filtration through
Celite, evaporation of the solvent and purification by
chromatography yields the corresponding diene.
In conclusion, we have shown a new entry to the
skeleton of steroids and aza- or oxa-steroids based on
the enyne metathesis reaction. The tetracyclic structure
is constructed in two steps from readily available eny-
nes. Other interesting skeletons like benzoazepines have
been obtained with good yields. A cascade metathesis-
Diels–Alder example is also shown.
1
9. Spectroscopic data for compound 8a: H NMR (CDCl3)
l 2.22 (s, 3H), 4.45 (bs, 2H), 5.30 (d, 1H, J=11.0 Hz),
5.58 (d, 1H, J=17.0 Hz), 6.18 (t, 1H, J=4.4 Hz), 6.56
(dd, 1H, J1=11.0 Hz, J2=17.0 Hz), 7.15–7.29 (m, 3H),
7.43 (d, 1H, J=7.7 Hz). 13C NMR (DMSO-d6, 80oC) l
168.2, 136.9, 134.1, 132.8, 128.1, 126.9, 124.7, 124.1,
124.0, 123.6, 116.3, 41.3, 21.6. IR (neat) w 1660, 1600,
1580.
Acknowledgements
10. (a) Schuster, T.; Kurz, M.; Go¨bel, M. W. J. Org. Chem.
2000, 65, 1697; (b) Garc´ıa Ruano, J. L.; Alemparte, C.;
Mart´ın Castro, A.; Adams, H.; Rodr´ıguez Ramos, J. J.
Org. Chem. 2000, 65, 7938.
11. Holder, R. W.; Matturro, M. G. J. Org. Chem. 1977,
42, 2166.
This work was supported by grants from the DGES
(MEC-Spain, PB98-0053) and the Universidad San
Pablo-CEU (grant 2/99). M.R.C. acknowledges the
DGES (MEC, Spain) for a predoctoral fellowship.
12. See Ref. 10 and also: Quinkert, G.; Del Grosso, M.;
Do¨ring, A.; Do¨ring, W.; Schenkel, R. I.; Bauch, M.;
Dambacher, G. T.; Bats, J. W.; Zimmermann, G.;
Du¨rner, G. Helv. Chim. Acta 1995, 78, 1345.
References
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